Early onset or syndromic epilepsy

Gene: EIF2S3

Green List (high evidence)

XLR MEHMO syndrome - mentasl retardation, epileptic seizures, hypogonadsm and hypogenitalism, microcephaly and obesity - life expectancy less than 2 years. Moortgat et al, 2016 - 2 teenage mat half brothers, unrelated Belgian parents - 1 developed seizures aged 9 months, the other didn't. A male infant from a second family - Spanish origin - onset of seizures at 10 months and died at 12 months, also 3 other male family members reported to have had a similar phenotype with early death2 diff hemizygous variants identified in these families - 1 missense and 1 fs - more severe pheno with this one. Skopkova et al, 2017 - 3 additional patients with MEHMO - 2 buys from nonconsang Slovakian families (both had epileptic seizures) and a 5 year old boy from nonconsang US family (no seizures) and also the original patient reported by Steinmuller et al, 1998 who had seizures - the same fs seen in 3 families and a missense in the other (milder pheno). 6 families in total 5/6 had seizures.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
MEHMO syndrome, 300148

Publications

• 27333055
• 28055140

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Comment on list classification: Updated rating from Amber to Green: Probable rating in Gene2Phenotype for 'Syndromic ID with severe microcephaly' but sufficient unrelated cases (>3) of seizures in MEHMO patients from literature (PMIDs 23063529,27333055,28055140).

Created: 29 Nov 2018, 10:43 a.m.

Comment on mode of inheritance: X-linked recessive MOI supported by OMIM and literature.

Created: 29 Nov 2018, 10:41 a.m.

Skopkova et al 2017 (PMID:28055140) identified a C-terminal frameshift mutation (Ile465Serfs) in the EIF2S3 gene in three families with MEHMO syndrome and a novel maternally inherited missense EIF2S3 variant (c.324T>A; p.Ser108Arg) in another male patient with less severe clinical symptoms. Two of the families had members with seizures amongst their phenotypes.

Created: 29 Nov 2018, 10:39 a.m.

Moortgat et al, 2016 (PMID:27333055) examined syndromic intellectual disability in two unrelated families with suspected X-linked inheritance. In both families, affected males presented with severe intellectual disability, microcephaly, growth retardation, and epilepsy in most individuals. A missense variant(c.777T>G p.(Ile259Met)) and a frameshift variant (c.1394_1397del p.(Ile465Serfs*4)) were identified in the EIF2S3 gene in the hemizygous state in affected patients, and in the heterozygous states female obligate carriers.

Created: 29 Nov 2018, 10:39 a.m.

Borck et al., 2012 (PMID:23063529) ascertained a family of Morocco Jewish ancestry in which three male individuals were affected by X-linked intellectual disability (ID). Individual III:2 had generalized seizures.

Created: 29 Nov 2018, 10:38 a.m.

Steinmuller et al 1998 (PMID:9781023) describe MEHMO syndrome with clinical hallmarks of mental retardation, epileptic seizures, hypogonadism, and -genitalism, microcephaly and obesity. They studied one large family with X-linked recessive inheritance (5 males affected, including 3 deceased and 1 terminated pregnancy). They don't identify the gene itself, but link the disease to a region of the X-chromosome.

Created: 29 Nov 2018, 10:30 a.m.

Green List (high evidence)

Seizures are a feature of this intellectual disability syndrome.

Created: 13 Aug 2018, 11:41 a.m.

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
MEHMO syndrome, MIM#300148

Publications

• 28055140, 27333055, 23063529

Variants in this GENE are reported as part of current diagnostic practice